Background: PF-07220060 is a novel potent oral CDK4-selective inhibitor with significant sparing of CDK6. We report the first disclosure of the first-in-human, multicenter trial of PF-07220060 alone or with endocrine therapy (ET). Methods: This Phase 1/2a study in advanced solid tumors was enriched for pts with HR+ HER2- advanced/metastatic breast cancer (HR+/HER2- mBC) who had received ≥2 lines of treatment including ET and CDK4/6 inhibitors (CDK4/6i). Prior fulvestrant and chemotherapy were allowed. Primary objective was to assess safety and tolerability of PF-07220060 alone and in combination with ET. Secondary/exploratory objectives included anti-tumor activity, pharmacokinetics (PK) and pharmacodynamics (PD). Results: At data cut off (Nov 1, 2022), 34 pts with advanced solid tumors received PF-07220060 in monotherapy dose escalation (Part 1A: 100–500 mg BID), and 26 pts with HR+/HER2- mBC in combination (300mg/400mg BID) with letrozole or fulvestrant (Parts 1B + 1C). For pts with HR+/HER2- mBC, median age was 61.5y (range 41–82y), ECOG PS was 0 (38.5% pts) or 1, and median prior lines of systemic therapy (advanced setting) 4.5 (range 1–11); all had prior CDK4/6i, 19 (73.1%) prior fulvestrant and 20 (76.9%) prior chemotherapy. Most frequent all causality treatment-emergent adverse events (TEAEs) with PF-07220060 + ET were diarrhea (50.0%; 0% G3), neutropenia (50.0%; 15.4% G3) and nausea (38.5%; 3.8% G3) with no >G3 TEAEs. A similar safety profile was seen in monotherapy. Dose-limiting toxicities occurred at PF-07220060 500 mg monotherapy BID (n=2 G3 thrombocytopenia) and at 400 mg BID + fulvestrant (n=1 G3 leukopenia/neutropenia). Preliminary PK analyses showed PF-07220060 is rapidly absorbed with dose-dependent increases in exposure. PF-07220060 300 mg BID was selected as the recommended dose for expansion. PD biomarker modulation was seen in tumor (pRB, Ki67 inhibition) and blood (TK1 inhibition). In pts with HR+/HER2- mBC with measurable disease who progressed on prior CDK4/6i+ET (n=21) treated with PF-07220060 (300/400 mg BID) + ET, confirmed RECIST v1.1 responses were observed in 6 (28.6%) pts (1 complete [CR], 5 partial [PR]). Clinical benefit response (CR, PR, or ≥24 wks stable disease) was seen in 11 (52.4%) pts. Median progression-free survival was 24.7 wks (95% CI: 23.1, 47.4). At data cutoff, 8/26 (30.8%) pts with mBC continued PF-07220060 + ET without progression for up to 60+ wks. Updated efficacy, PK, PD, and biomarker data will be presented. Conclusions: PF-07220060 + ET showed efficacy in pts with HR+/HER2- mBC who progressed on prior CDK4/6i+ET. Tolerability of PF-07220060 alone and in combination with ET was encouraging. Dose expansions with PF-07220060 + ET in pts with HR+/HER2- mBC post CDK4/6i and in CDK4/6i naïve pts are ongoing. Clinical trial information: NCT04557449.